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      The reticulons: a family of proteins with diverse functions

      Genome Biology
      BioMed Central

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          Abstract

          The reticulon family is a diverse group of proteins that mostly localize to the endoplasmic reticulum and may be important in neurodegenerative diseases.

          Abstract

          The reticulon family is a large and diverse group of membrane-associated proteins found throughout the eukaryotic kingdom. All of its members contain a carboxy-terminal reticulon homology domain that consists of two hydrophobic regions flanking a hydrophilic loop of 60-70 amino acids, but reticulon amino-terminal domains display little or no similarity to each other. Reticulons principally localize to the endoplasmic reticulum, and there is evidence that they influence endoplasmic reticulum-Golgi trafficking, vesicle formation and membrane morphogenesis. However, mammalian reticulons have also been found on the cell surface and mammalian reticulon 4 expressed on the surface of oligodendrocytes is an inhibitor of axon growth both in culture and in vivo. There is also growing evidence that reticulons may be important in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. The diversity of structure, topology, localization and expression patterns of reticulons is reflected in their multiple, diverse functions in the cell.

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          A class of membrane proteins shaping the tubular endoplasmic reticulum.

          How is the characteristic shape of a membrane bound organelle achieved? We have used an in vitro system to address the mechanism by which the tubular network of the endoplasmic reticulum (ER) is generated and maintained. Based on the inhibitory effect of sulfhydryl reagents and antibodies, network formation in vitro requires the integral membrane protein Rtn4a/NogoA, a member of the ubiquitous reticulon family. Both in yeast and mammalian cells, the reticulons are largely restricted to the tubular ER and are excluded from the continuous sheets of the nuclear envelope and peripheral ER. Upon overexpression, the reticulons form tubular membrane structures. The reticulons interact with DP1/Yop1p, a conserved integral membrane protein that also localizes to the tubular ER. These proteins share an unusual hairpin topology in the membrane. The simultaneous absence of the reticulons and Yop1p in S. cerevisiae results in disrupted tubular ER. We propose that these "morphogenic" proteins partition into and stabilize highly curved ER membrane tubules.
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            Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein.

            Adult mammalian axon regeneration is generally successful in the peripheral nervous system (PNS) but is dismally poor in the central nervous system (CNS). However, many classes of CNS axons can extend for long distances in peripheral nerve grafts. A comparison of myelin from the CNS and the PNS has revealed that CNS white matter is selectively inhibitory for axonal outgrowth. Several components of CNS white matter, NI35, NI250(Nogo) and MAG, that have inhibitory activity for axon extension have been described. The IN-1 antibody, which recognizes NI35 and NI250(Nogo), allows moderate degrees of axonal regeneration and functional recovery after spinal cord injury. Here we identify Nogo as a member of the Reticulon family, Reticulon 4-A. Nogo is expressed by oligodendrocytes but not by Schwann cells, and associates primarily with the endoplasmic reticulum. A 66-residue lumenal/extracellular domain inhibits axonal extension and collapses dorsal root ganglion growth cones. In contrast to Nogo, Reticulon 1 and 3 are not expressed by oligodendrocytes, and the 66-residue lumenal/extracellular domains from Reticulon 1, 2 and 3 do not inhibit axonal regeneration. These data provide a molecular basis to assess the contribution of Nogo to the failure of axonal regeneration in the adult CNS.
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              Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.

              Nogo has been identified as a component of the central nervous system (CNS) myelin that prevents axonal regeneration in the adult vertebrate CNS. Analysis of Nogo-A has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the endoplasmic reticulum lumen of transfected cells and oligodendrocytes. The acidic amino terminus of Nogo-A is detected at the cytosolic face of cellular membranes and may contribute to inhibition of axon regeneration at sites of oligodendrocyte injury. Here we show that the extracellular domain of Nogo (Nogo-66) inhibits axonal extension, but does not alter non-neuronal cell morphology. In contrast, a multivalent form of the N terminus of Nogo-A affects the morphology of both neurons and other cell types. Here we identify a brain-specific, leucine-rich-repeat protein with high affinity for soluble Nogo-66. Cleavage of the Nogo-66 receptor and other glycophosphatidylinositol-linked proteins from axonal surfaces renders neurons insensitive to Nogo-66. Nogo-66 receptor expression is sufficient to impart Nogo-66 axonal inhibition to unresponsive neurons. Disruption of the interaction between Nogo-66 and its receptor provides the potential for enhanced recovery after human CNS injury.
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                Author and article information

                Journal
                Genome Biol
                Genome Biology
                BioMed Central
                1465-6906
                1465-6914
                2007
                28 December 2007
                : 8
                : 12
                : 234
                Affiliations
                [1 ]Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA
                Article
                gb-2007-8-12-234
                10.1186/gb-2007-8-12-234
                2246256
                18177508
                266dcfd6-a11e-46f0-84b0-cb1637f62c77
                Copyright © 2007 BioMed Central Ltd
                History
                Categories
                Protein Family Review

                Genetics
                Genetics

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